Primary open-angle glaucoma (POAG) is the leading cause of chronic optic neuropathy and a major source of ocular morbidity worldwide. Understanding preclinical events, early phase disease and disease heterogeneity represent key objectives in early disease detection, prevention and treatment of POAG. In this study, we propose 4 specific aims. 1) We will perform both targeted and untargeted metabolome-wide association studies (MWAS) for POAG using pre-clinical serum from a large case-control group (500 cases and 500 controls) nested within ongoing prospective studies of the Nurses' Health Study (NHS), NHS2, and Health Professionals Follow-up Study (HPFS) to advance our understanding of the biochemical events that precede POAG diagnosis (blood was collected ~ 10 years prior to disease diagnosis). Prior studies suggest that nitric oxide metabolites represent genetically informed markers and will form the basis for targeted profiling. 2) While considerable discoveries have been made of POAG genes, more work is needed to leverage genome-wide information to inform POAG etiology. Thus, we will create a genome-wide genetic correlation matrix between POAG and complex traits previously linked to POAG, using data from the NEIGHBORHOOD (National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database; 3800 POAG cases) consortium and publicly available summary genome-wide association study data. An assessment of the shared heritability between POAG and these traits as well as the relation between the genetic risk scores for these traits and POAG will lead to new etiologic insights. 3) New-onset POAG is clinically heterogeneous with variable visual field (VF) loss patterns that may reflect different etiologies. We will apply archetype analysis, which objectively quantifies a patient's VF loss pattern to 16 existing clinically validated archetypes (ATs), 9 of which are glaucomatous in nature. Each POAG case (n=1250 from NHS, NHS2 and HPFS) and10 matched controls will be assigned 16 weighted coefficients that add up to 1, with each value representing how consistent his / her VF loss pattern is with each glaucomatous AT. We will evaluate the differential relation between established POAG risk factors and the values on the 16 ATs, to identify unique risk factors for homogeneous incident POAG subtypes. 4) A carbohydrate-restricted diet may meet the energy requirement in the non-myelinated retinal ganglion cell axon segment of the optic nerve and reduce risk of POAG. We will conduct a prospective evaluation of this exposure in relation to POAG and POAG subtypes in the 3 cohorts (n=2100 cases). By integrating MWAS, genomics with prospective environmental exposure data and AT analysis, this proposal addresses a number of important knowledge gaps?in particular, it will shed light on how genetic and pre-diagnostic risk factors influence POAG and POAG heterogeneity. Linking specific exposures with POAG subtypes will provide important mechanistic understanding as well as evidence of causality, which will contribute to discovering precision medicine approaches for this condition.